Recurrent Epithelial Ovarian Cancer, Recurrent Fallopian Tube Cancer, Recurrent Primary Peritoneal Cancer
Conditions
Keywords
Cancer, Recurrent, Ovary, Fallopian Tube, Primary Peritioneal, Phase II, Platinum Resistant
Brief summary
This phase II trial studies how well tivozanib works in treating patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer. Tivozanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES: I. To determine the clinical activity of tivozanib in patients with platinum-resistant, recurrent ovarian, fallopian tube or primary peritoneal cancer. SECONDARY OBJECTIVES: I. Determining the potential survival advantage and characterizing the safety of single agent tivozanib in patients with platinum-resistant ovarian cancer. OUTLINE: Patients receive tivozanib hydrochloride orally (PO) once daily (QD) on days 1-21. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Interventions
DRUGTivozanib
1.5 mg Given PO (orally)days 1-21 or every 28 day cycle
Sponsors
National Comprehensive Cancer Network
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 110 Years
Healthy volunteers
No
Inclusion criteria
* • Patients must have recurrent or persistent, platinum resistant epithelial ovarian, fallopian tube or primary peritoneal carcinoma; platinum-resistant disease is defined as a recurrence within 6 months of completing adjuvant, platinum-based chemotherapy * Patients must have measurable disease or non-measurable (detectable) disease: * Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be greater than or equal to 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or by clinical exam; or greater than or equal to 20 mm when measured by chest x-ray; lymph nodes must be greater than or equal to 15 mm in short axis when measured by CT or MRI * Non-measurable (detectable) disease in a patient is defined in this protocol as one who does not have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria but does have a cancer antigen 125 (CA-125) greater than or equal to two times the upper normal limit within the last 60 days (confirmatory at baseline) and at least one of the following conditions: * Ascites and/or pleural effusion attributed to tumor * Hypermetabolic lesions on positron emission tomography (PET) scan * Patients with measurable disease must have at least one target lesion to be used to assess response on this protocol as defined by RECIST * Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 * Recovery from effects of recent surgery, radiotherapy, or chemotherapy: * Patients should be free of active infection requiring antibiotics (with the exception of uncomplicated urinary tract infection \[UTI\]) * Any other prior therapy directed at the malignant tumor, including chemotherapy, biological/targeted (non-cytotoxic) agents and immunologic agents, must be discontinued at least three weeks prior to registration * At least 4 weeks must have elapsed since the patient underwent any major surgery (e.g., major: laparotomy, laparoscopy, thoracotomy, video assisted thorascopic surgery (VATS); there is no restriction on minor procedures (e.g., minor: central venous access catheter placement, ureteral stent placement or exchange, paracentesis, thoracentesis) * Patients must have had one prior taxane and platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organo platinum compound; this initial treatment may have included intraperitoneal therapy, consolidation, non-cytotoxic (biologic/targeted agents, such as bevacizumab) or extended therapy administered after surgical or non-surgical assessment; there is no maximum number of prior regimens; * patients may not have had any prior systemic therapy (including interleukin-2, interferon-alpha, chemotherapy, bevacizumab, investigational or licensed drug that targets vascular endothelial growth factor \[VEGF\] or VEGF receptors/pathway or are mammalian target of rapamycin \[mTOR\] inhibitors) for treatment of recurrent ovarian cancer * Patients must have signed an approved informed consent and authorization permitting the release of personal health information * Patients must meet pre-entry requirements * A female is eligible to participate if she is of non-childbearing potential or as documentation of a negative pregnancy test prior to the start of the study treatment; sexually active pre-menopausal female subjects must agree to use adequate, highly effective contraceptive measures, while on study and for 45 days after the last dose of last study drug; effective birth control includes (a) intrauterine device (IUD) plus one barrier method; (b) oral, implantable or injectable contraceptives plus one barrier method; or (c) 2 barrier methods; effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm)
Exclusion criteria
* • Age \< 18 years * Patients who have had previous treatment with tivozanib * Hemoglobin \< 9.0 g/dL * Absolute neutrophil count (ANC) \< 1500 per mm\^3 * Platelet count \< 100,000 per mm\^3 * Total bilirubin \> 1.5 × upper limit of normal (ULN) (or \> 2.5 x ULN for subjects with asymptomatic Gilbert's syndrome) * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2.5 × ULN (or \> 5 × ULN for subjects with liver metastasis) * BOTH total bilirubin \> ULN AND AST/ALT \> ULN * Alkaline phosphatase \> 2.5 × ULN (or \> 5 × ULN for subjects with liver or bone metastasis) * Creatinine \> 2.0 × ULN * Prothrombin time (PT) such that international normalized ratio (INR) \> 1.5 x ULN (unless a patient is on therapeutic warfarin) or a partial thromboplastin time (PTT) \> 1.5 x ULN * Proteinuria \> 3+ by urinalysis or urine dipstick * Significant cardiovascular disease, including: * Symptomatic left ventricular dysfunction or baseline left ventricular ejection fraction (LVEF) by multigated acquisition scan (MUGA) or echocardiogram (ECHO) of =\< lower limit of institutional normal (LLN) * Uncontrolled hypertension: systolic blood pressure of \> 140 mmHg or diastolic blood pressure of \> 90 mmHg documented on 2 consecutive measurements taken at least 24 hours apart * Myocardial infarction, severe angina, or unstable angina within 6 months prior to administration of first dose of study drug * History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) * Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with anti-arrhythmic medication) * Coronary or peripheral artery bypass graft within 6 months of screening * History of class III or IV congestive heart failure, as defined by the New York Heart Association * Central nervous system metastases; Note: subjects with previously treated (radiotherapy or surgery) brain metastasis that have been stable without steroid treatment for at least 3 months following prior treatment may be enrolled * Non-healing wound, bone fracture, or skin ulcer * Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal condition with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to administration of first dose of study drug * Serious/active infection or infection requiring parenteral antibiotics * Corrected QT interval (QTc) of \> 480 msec using Bazett's formula * Radiotherapy or minor surgical procedure within 2 weeks, or major surgical procedure within 4 weeks prior to administration of first dose of study drug; inadequate recovery from prior surgical procedure * Significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug, including but not limited to: * Deep vein thrombosis * Pulmonary embolism * Cerebrovascular accident (CVA) or transient ischemic attack (TIA) * Peripheral arterial ischemia \> grade 2 (per National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version 4.0) * Significant bleeding disorders within 6 months prior to administration of first dose of study drug, including but not limited to: * Hematemesis, hematochezia, melena or other gastrointestinal bleeding \>= grade 2 (per CTCAE version 4.0) * Hemoptysis or other pulmonary bleeding \>= grade 2 (per CTCAE Version 4.0) * Hematuria or other genitourinary bleeding \>= grade 2 (per CTCAE Version 4.0) * Currently active second primary malignancy, including hematologic malignancies (leukemia, lymphoma, multiple myeloma, etc.), other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, and ductal or lobular carcinoma in situ of the breast; subjects are considered to have a currently active malignancy if they have completed anti-cancer therapy and have not been disease free for \> 2 years * Pregnant or lactating females * History of genetic or acquired immune suppression disease such as human immunodeficiency virus (HIV); subjects on immune suppressive therapy for organ transplant * Life-threatening illness or organ system dysfunction compromising safety evaluation * Requirement for hemodialysis or peritoneal dialysis * Inability to swallow capsules, malabsorption syndrome or gastrointestinal disease that severely affects the absorption of study drugs, major resection of the stomach or small bowel, or gastric bypass procedure * Known hypersensitivity to drugs chemically related to tivozanib hydrochloride or sunitinib or their excipients * Psychiatric disorder or altered mental status precluding informed consent or protocol-related testing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Time taken to reach first best response. Range 1-4 cycles (1 cycle = 28 days) | ORR is defined as the number of patients with complete response plus those with partial response as measured by RECIST 1.1 where: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Up to 36 months | The Kaplan-Meier method will be utilized to estimate the median and overall distribution of PFS and will be defined from the start of treatment until the first documentation of progressive disease or death, whichever occurs first.. |
| Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | During treatment and up to 30 days after completion of study treatment. Range of cycles 1-32 (1 cycle =28 days). | Adverse events will be assessed by NCI CTCAE v 4.03. Adverse event that were determined to be serious adverse events (either grade 3, 4, or 5) related to study drug were collected. Grading is as follows:In general the following severity definitions are true: Mild (grade 1): the event causes discomfort without disruption of normal daily activities. Moderate (grade 2): the event causes discomfort that affects normal daily activities. Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Life-threatening (grade 4): the patient was at risk of death at the time of the event. Fatal (grade 5): the event caused death. |
| Overall Survival (OS) in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Up to approximately 42 months | OS is defined from the start of treatment until date of death from any cause or date of last contact. |
Countries
United States
Participant flow
Recruitment details
The study opened to enrollment on May 23, 2013 with the first patient being enrolled and treated on the study on June 6, 2013. The study closed to further enrollment August 10, 2018 with 31 patients registered to the study and 30 patients treated on study.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Tivozanib) Tivozanib 1.5mg orally given daily for 3 weeks with one week off to complete a 4 week cycle until disease progression or adverse effects prohibit further therapy
Tivozanib: 1.5 mg Given PO (orally)days 1-21 or every 28 day cycle | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Continued Treatment After First Response | Adverse Event | 2 |
| Continued Treatment After First Response | Progressive Diseaes | 10 |
| Reached First Response/Complete 2 Cycles | Adverse Event | 2 |
| Reached First Response/Complete 2 Cycles | Other | 1 |
| Reached First Response/Complete 2 Cycles | Progressive Disease | 2 |
| Reached First Response/Complete 2 Cycles | Withdrawal by Subject | 1 |
| Registration and Treatment Start | Did not start treatment | 1 |
Baseline characteristics
| Characteristic | Treatment (Tivozanib) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 28 Participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 30 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 28 / 30 |
| other Total, other adverse events | 30 / 30 |
| serious Total, serious adverse events | 12 / 30 |
Outcome results
Primary
Overall Response Rate (ORR)
ORR is defined as the number of patients with complete response plus those with partial response as measured by RECIST 1.1 where: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Time taken to reach first best response. Range 1-4 cycles (1 cycle = 28 days)
Population: 6 patients who were determined to not be evaluable and are not included in the overall number of patients analyzed
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Tivozanib) | Overall Response Rate (ORR) | 4 participants |
Secondary
Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib
Adverse events will be assessed by NCI CTCAE v 4.03. Adverse event that were determined to be serious adverse events (either grade 3, 4, or 5) related to study drug were collected. Grading is as follows:In general the following severity definitions are true: Mild (grade 1): the event causes discomfort without disruption of normal daily activities. Moderate (grade 2): the event causes discomfort that affects normal daily activities. Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Life-threatening (grade 4): the patient was at risk of death at the time of the event. Fatal (grade 5): the event caused death.
Time frame: During treatment and up to 30 days after completion of study treatment. Range of cycles 1-32 (1 cycle =28 days).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Tivozanib) | Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Stroke | 1 Participants |
| Treatment (Tivozanib) | Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Hypertension | 8 Participants |
| Treatment (Tivozanib) | Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Fatigue | 3 Participants |
| Treatment (Tivozanib) | Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Hyponatremia | 2 Participants |
| Treatment (Tivozanib) | Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Colonic Fistula | 2 Participants |
| Treatment (Tivozanib) | Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Nausea | 1 Participants |
| Treatment (Tivozanib) | Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Hypomagnesemia | 1 Participants |
| Treatment (Tivozanib) | Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Anemia | 1 Participants |
| Treatment (Tivozanib) | Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Proteinuria | 1 Participants |
| Treatment (Tivozanib) | Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Hypoalbuminemia | 1 Participants |
| Treatment (Tivozanib) | Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Small intestinal perforation | 1 Participants |
| Treatment (Tivozanib) | Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Portal hypertension | 1 Participants |
| Treatment (Tivozanib) | Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Small intestinal obstruction | 1 Participants |
Secondary
Overall Survival (OS) in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib
OS is defined from the start of treatment until date of death from any cause or date of last contact.
Time frame: Up to approximately 42 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Tivozanib) | Overall Survival (OS) in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | 8.64 months |
Secondary
Progression Free Survival (PFS) in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib
The Kaplan-Meier method will be utilized to estimate the median and overall distribution of PFS and will be defined from the start of treatment until the first documentation of progressive disease or death, whichever occurs first..
Time frame: Up to 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Tivozanib) | Progression Free Survival (PFS) in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | 4.06 months |
Post Hoc
3, 6 and 12 Month Overall Survival Probability
OS is defined from the start of treatment until date of death from any cause or date of last contact with the probability being calculated at 3, 6 and 12 months.
Time frame: At 3, 6 and 12 months from initiation of treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Tivozanib) | 3, 6 and 12 Month Overall Survival Probability | 3 months | 0.867 probability of patients alive |
| Treatment (Tivozanib) | 3, 6 and 12 Month Overall Survival Probability | 6 months | 0.633 probability of patients alive |
| Treatment (Tivozanib) | 3, 6 and 12 Month Overall Survival Probability | 12 months | 0.400 probability of patients alive |
Post Hoc
3, 6, and 12 Month Progression Free Survival
PFS rate will be measured by the number of patients that are progression free at 3, 6 and 12 months from treatment initiation.
Time frame: at 3, 6 and 12 months from start of treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Tivozanib) | 3, 6, and 12 Month Progression Free Survival | 12 months | 0.067 probability of patients progression free |
| Treatment (Tivozanib) | 3, 6, and 12 Month Progression Free Survival | 3 months | 0.567 probability of patients progression free |
| Treatment (Tivozanib) | 3, 6, and 12 Month Progression Free Survival | 6 months | 0.267 probability of patients progression free |
Post Hoc
Clinical Benefit Rate (CBR)
CBR is defined as the number of patients with Complete Response (CR) plus those with Partial Response (PR) plus those with Stable Disease (SD) as assessed by RECIST 1.1 where: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: Time taken to reach first best response. Range 1-4 cycles (1 cycle = 28 days)
Population: 6 patients were determined to be not evaluable are not included in the overall number of patients analyzed
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Tivozanib) | Clinical Benefit Rate (CBR) | 18 participants |
Post Hoc
Duration of Response
Duration of response is defined as the time of response to the time of progression for those patients who responded. Response is generally defined as either: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.
Time frame: During treatment and up to 30 days after completion of study treatment. Range of cycles 1-32 (1 cycle =28 days).
Population: Only patients with a response are included
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Tivozanib) | Duration of Response | 5.7 months |
Post Hoc
Overall Best Response of Patients With Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib
Overall Best Response as measured by physical exam findings, serum CA125 levels and/or measurement of index lesions via appropriate imaging studies using RECIST criteria defined as either: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: Time taken to reach first best response. Range 1-4 cycles (1 cycle = 28 days)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Tivozanib) | Overall Best Response of Patients With Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | CR | 0 Participants |
| Treatment (Tivozanib) | Overall Best Response of Patients With Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | PR | 4 Participants |
| Treatment (Tivozanib) | Overall Best Response of Patients With Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | SD | 14 Participants |
| Treatment (Tivozanib) | Overall Best Response of Patients With Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | PD | 6 Participants |
| Treatment (Tivozanib) | Overall Best Response of Patients With Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Not Evaluable | 6 Participants |